In the current project, genetic determinants of type 2 diabetes mellitus and obesity are being sought using techniques of genetic linkage and association analysis. Lymphoblast cell lines have been established from informative pedigrees. DNA is available from other families in nuclear pellets extracted from blood specimens obtained in the epidemiologic studies and is amplified by whole genome amplification when needed. An autosomal genome-wide linkage study identified strong evidence for a locus influencing both obesity and diabetes on chromosome 11q. Evidence for an additional locus influencing diabetes and insulin secretory function was found on chromosome 1q. Efforts to identify the causative polymorphism or polymorphisms in both of these regions are currently underway using both a systematic analysis of linkage disequilibrium and analyses of candidate genes. Genome-wide association mapping methods are also being used and exhaustive association analyses are being conducted of candidate genes.[unreadable] [unreadable] Several regions that appear to be in linkage disequilibrium with obesity-susceptibility alleles on chromosome 11 have been identified and several candidate genes have been analyzed. In collaboration with the Sanger Centre a dense (5 kb) linkage disequilibrium map of chromosome 1q is being generated for Pimas and for several other populations that have shown linkage to this region (the International 1q Type 2 Diabetes Consortium). There are several regions that appear to be associated with risk of type 2 diabetes in Pimas or other populations, but these do not include the candidate genes USF1 or LMNA. Several candidate genes that have been associated in other populations (including TCF7L2, the variant with the strongest association in most populations identified to date) do not show strong associations in the Pimas. Recently a genome-wide association study with 100,000 markers has identified several additional potential susceptibility genes for young-onset diabetes.[unreadable] [unreadable] Currently fine-mapping studies with additional variants are being conducted to extract more of the genetic information in regions identified as potentially involved in diabetes susceptibility. Through collaborations, studies are being conducted to determine if any of the signals identified in the present mapping studies replicate in other populations. Variants reproducibly associated with type 2 diabetes from other populations are also being typed to determine their role susceptibilty to diabetes and obesity in the Pimas. A more dense genome-wide association is currently underway.